2-Methyl-2-{8 2-(1,2,3,4,-tetrahydro-9-methyl carbazol-4-ylidene)-ethyl{9 1,3-cyclopentane dione

ABSTRACT

Indolosteroids having the following formulas are disclosed   These compounds are useful as an adjunct in skin grafts.

United States Patent [191 Sircar et al.

[ 2-METHYL-2-I 2-( l,2,3,4,-TETRAHYDRO-9- METHYLCARBAZOL-4-YLIDENEl-ETHYL]1,3- CYCLOPENTANE DIONE [75l lnventors'.Jagadish C. Sircar. Dover; Harold Zinnes, Rockaway, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

221 Filed: Feb. 18, 1975 211 Appl. No.1550,333

Related US. Application Data loll Diflsion of Ser. NOv 475559. June 3.I974.

[52} US. Cl 260/240 R; 260/315. 424/274 [5 l] Int. Cl? C07D 209/86 [58]Field of Search 260/240 R, 315

[56} References Cited OTHER PU BLlCATlONS lrmmr Examiner-Sherman D.Winters Ammw Agent, or Firm-Albert H. Graddis; Frank S. Chow [1113,919,203 Nov. 11, 1975 {5 7 ABSTRACT lndolosteroicls having thefollowing formulas are disclosed These Compounds are useful as anadjunct in skin grafts.

1 Claim, N0 Drawings 1 2 2-METHYL-2-l 2-( l,Z,3,4-'IETRAl-IYBRO-9- Thepresent invention relates to indolosteriodsi More METHYL specificallythe present invention relates to 6,12a- CARBAZOL-4-YLIDENE)-ETHYL]I,3-dimethylindeno-[4,5cl-carbazoles of the formulas:

CYCLOPENTANE DIONE CH3 CH3 i l N H N CH; C:

I II

This is a division, of application Ser. No. 475,559 Br adly peak ng. theabove compounds are prefiled June 3, 1974. pared according to thefollowing reaction scheme:

0 CH=CH CHz'CHLi l N 3 cu III V VI N CH3 VII Rcney Ni N CH;

Referring to the above scheme, 9-methyl-4ketol,2,3,4-tetrahydrocarbazoleIII is reacted with vinyllithium in a solvent such as tetrahydrofuran togive IV. This is reacted with 2-methylcyclopentanedione using a strongbasic catalyst such as benzyltrimethylammonium hydroxide availablecommercially as Triton B (J. T. Baker Co., Eastman Kodak, etc.) to givea mixture of V and VI, the latter being the predominant product. Both Vand VI undergo facile dehydration in the presence of acids such ashydrochloric acid or p-toluenesulfonic acid to form Vll. Reduction witha complex metal hydride such as sodium borohydride of VII gives thealcohol VII which is converted to compound I by stirring with RaneyNickel catalyst in a solvent such as tetrahydrofuran. Compound II isobtained by passing a stream of oxygen through a solution of VII in asolvent such as a mixture of alcohol and chloroform.

The starting compound III is prepared as described by H. J. Teuber andD. Cornelius, Ann. Chem. 671; 127 (1964).

The compounds of the invention are useful as adjunct agents in skingraft therapy. For example, they exhibit the property to prolong thesurvival of allografts in laboratory animals such as mice. Thus at ani.p. dose of 5 mg/kg to 100 mg/kg they prolong the life span ofallografts in mice.

They are indicated as an adjunct in skin graft therapy to suppress hostrejection of the graft within the above dose range. This dose can bevaried depending upon the condition of the host being treated.

These compounds are administered subcutaneously or intramuscularly indosage forms suitable for such administration. For example, they arecombined with a vehicle such as a peanut oil, sesame oil and compoundedwith dosage forms by known pharmaceutical technology.

In order to illustrate further the practice of the present invention.the following examples are included.

EXAMPLE 1 cu=ca,

4-Hydroxy-9-methyl-4-vinyl-1,2,3,4-

tetrahydrocarbazole. A suspension of 67 g (0.33 mol) of4Jceto-9-methyl-l,2,3,4-tetrahydrocarbazole in 1700 ml oftetrahydrofuran was cooled to -l0 and L0 mol (as a 2.9 molar solution intetrahydrofuran) of vinyllithium was added over a 75 min period. Thereac- VIII tion mixture was allowed to slowly warm up to roomtemperature, stirred for 2 hr, decomposed with icewater, and extractedwith dichloromethane. The dichloromethane solution was concentrated to asmall volume (not to dryness) and an oil separated from solution. Theupper solvent layer was decanted from the oil and the latter wastriturated with ether to give 60 g of product, mp 9 l-95 dec, which wasof sufficient purity for use as an intermediate for further reactions. Apor tion was dissolved in tetrahydrofuran and petroleum ether was addedtill crystals separated. The first crop (mp 93) was filtered off and themother liquor was concentrated to give a second crop, mp 96 dec. Thissecond crop was recrystallized in the same manner to give an analyticalsample, mp 9597dec.

Anal. Calcd for C H NO: C, 79.26; H, 7.54; N. 6.16. Found: C. 79.30; H,7.72; N, 6.18. v"'3300, 1610, 1558 cm".

EXAMPLE 2 l on 3,3a,4.5,6,1 l,12,12a-Octahydro-6,12a-dimethyl-3-hydroxyindene [4,5c]-carbazol-1(2H)-one. To a solution of 56.8 g (0.25mol) of 4-hydroxy-9-methyl-4- vinyl-l,2,3,4-tetrahydrocarbazole in amixture of 500 ml of xylene and 150 ml of tert-butanol was added 28.1 g(0.25 mol) of Z-methylcyclopentan-l,3-dione. The mixture was stirred atroom temperature for IS minutes, 10.8 ml of 40% methanolic Triton B wasadded, and it was refluxed under a nitrogen atmosphere for 3 hr, using aDean-Stark separator to remove the water which formed during thereaction. The reaction mixture was filtered away from insolubleunreacted 2- methyl-cyclopentan-l,3-dione and the filtrate was washedsuccessively with 5% potassium hydroxide solution, aqueous sodiumchloride solution, and water. The dried (Na S0 organic layer wasconcentrated to a volume of about 200 ml and diluted with 500 ml ofether. The resulting precipitate (52 g) was collected and stirred atroom temperature, under nitrogen. for 30 min with 450 ml ofdichloromethane. The insoluble component (3.8 g) was collected andpurified by dissolving in 250 ml of tetrahydrofuran, concentrating theresulting solution to 100 ml and diluting with 100 ml of ether. Theresulting crystalline product, mp l75l80dec. weighed 3.2 g

Anal Calcd for c n no C, 78.47; H, 7.21; N, 4.36. Found: C,78.15; H,7.33; N, 4.20. 1 "3450, 1718, 1650, 1604 cm".

EXAMPLE 3 Cl-l,

2-Methyl-2[2-(1,2,3,4-tetrahydro-9-methylcarbazol-4-ylidene)-ethyl]-l,3-cyclopentanedione. The dichloromethane filtrate fromthe previously described experiment was concentrated to a small volumeand diluted with ether to cause precipitation of 45 g of product, mp165l 70 dec (material turned green at 95 and shrank at about 155 beforemelting). This material was sufficiently pure for use as an intermediatefor subsequent reactions. An analytical sample was obtained byredissolving a portion in dichloromethane and diluting with ether; ithad mp l75-178 dec (turned green at 95 and shrank at 158).

Anal. Calcd for C H NO C, 78.47; H, 7.21; N, 4.36. Found: C, 78.32; H,7.15; N, 4.52.

v''1758,1715,1637, 1605 cm. It is readily distinguished from the productof the previous example by its faster mobility on thin layerchromatography using aluminum oxide plates with 2-butanoneheptane (3:1)as the eluant.

Evaporation of the original xylene-ether filtrate (see previous example)and recrystallization of the residue from dichloromethaneether gave 7.6g of additional product, mp 168l72 dec (turned green at 97).

EXAMPLE 4 4,5,6,l1,12,l2a-Hexahydro-6,lZa-dimcthylindeno-[4,5-cl-carbazol-1(2H)-one Method A A mixture of 48.0 g (0.15 mol) of2-[2-(1.2.3.4-tetrahydro-9-methylcarbazoI-4-ylidene)-ethy1l-2-methylcyclopentane-1,3-dione, 2.4 gof p-toluenesulfonic acid and 1500 ml of benzene was refluxed under anitrogen atmosphere for min during which time the theoretical yield ofwater was collected in a Dean Stark water separator. The reactionmixture was cooled and the dark green solution was decanted from a tarryresidue. This solution was diluted with dichloromethane, washedsuccessively with sodium carbonate, water, and saturated sodium chloridesolution, dried over sodium sulfate, and evaporated to dryness. Theresulting yellow solid was recrystallized fromdichloromethaneacetonitrile to give 30 g of product, mp 195197dec.

Anal. Calcd for C H NO: C,83.13; H, 6.98; N, 4.62. Found: C, 82.91; H,6.96; N, 4.58. 121738, 1604, I535. )t,,,,, 248 (21,000), 284 (12,500),330(e12,800) m Concentration of the mother liquor and dilution withether gave 7.0 g of a less pure second crop, mp 183-l90 dec.

EXAMPLE 4 (Continued) Method B. To a mixture of 1.07 g (0.0033 mol) of3,- 3a,4,5,6,l1,12,12a-octahydro-6,12a-dimethyl-3-hydroxyindene[4,5c]-carbazol-l (2H )-one and 60 ml of tetrahydrofuranwas added I2 ml of 18% hydrochloric acid. The resulting clear solutionwas allowed to stand at room temperature for 21 hr, concentrated underreduced pressure to one-third its volume, and slowly poured into icecold saturated sodium carbonate solution. The mixture was stirred atice-bath temperature for 30 min and the resulting yellow solid wascollected, washed well with water and dried in vacuo over phosphorouspentoxide. This solid (1.04 g, mp 175-182 dec) was recrystallizedseveral times from acetonitrile to give 463 mg of product, mp 193"195dec.

meta

1,2,4,5,6,11,12,]2a-Oetahydro-6,12a-dimethyl-lhydroxyindeno-{4,5c]-carbazole.To a suspension of 10.0 g (0.033 mol) of 4,5,6,11,12,l2ahexahydro-6,lZa-dimethylindeno-l4,5-c]-carbazo1-1(2H)-one in 375 ml of ethanol wasadded 4.1 g of sodium borohydride followed by 25 ml of water. Themixture was stirred at room temperature for 20 hr, 600 ml of water wasadded, and it was stirred an additional 3 hr. The re sulting precipitatewas collected and dried in vacuo over P 0 to give 10 g of product, mp179-181 dec which was sufficiently pure for use as an intermediate forsubsequent reactions. Recrystallization by dissolving in tetrahydrofuranand diluting with ether gave 6.9 g of material, mp 178-180 dec.

Anal. Calcd for C H NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 82.45; H,7.47; N, 4.62. v" "'3430, 1608, 1540, 1535 cm". A,,,,,,248 (62,400), 283(18,200), 296 (14,000), 312 (15,800), 325 (17,000)

EXAMPLE 6 N ii l,2,3,3a,6.l l.l 2,l2a-Octahydro-6,l2a-dimethyl-lhydroxyindeno-[4,5c]-carhazole. A mixture of l0.0 g (0.033mol) of l 2 4.5,6,l l,l 2,l2a-octahydro-6,l 2adimethyl-l-hydroxyindeno-[4,5c)carbazle, 5 g of W7 Raney Nickel catalystand 350 ml of tetrahydrofuran was stirred vigorously at room temperatureunder a nitrogen atmosphere for 6 hr. and then allowed to stand overnight. The catayst was filtered off, the solvent was evaporated, and thesolid residue was triturated with ether to give 87 g of crystallineproduct, mp 2l722ldec. Recrystallization from dichloromethane-methariolto give 5.) g of material, mp 22022l dec.

Anal. Caled for C H NOI C, 8259; H. 7.59; N, 4.59. Found: 82.47; H,7.63; N. 4.34. "'3260 i582,

1475 cm. A,,,,,,242 (46,000), 268 (24,000). 293 (17.600). 352 (0.000).

EXAMPLE 7 6,1l,l2,12a-Tetrahydro-6,lZ-a-dimethylindeno-(4,5-cl-carbazol-H2H J-one. A stream of oxygen was passed through asolution of 5.0 g (0.0165 mol) M45,- 6,] l,l2,l2a-hexahydro(i,I2a-dimethylindeno[4 5c)- carhuzol-l (2H)one in a mixture of 300 mlof chloroform and 300 ml of ethanol for 48 hr. It was concentrated to avolume of about 200 ml and the resulting precipitate was collectedwashed with ether, and dried to give 2.2 g of pink crystalline solid. mp230 240". Recrystallization by dissolving in dichloromethane anddilution with acetonitrile gave 1.6 g of pink crystalline product, mp243-246 dec. Another recrystallization gave an analytical sample, mp244246dec.

Anal. Calcd for C H NO: C. 83.69; H, 6.35; N. 4.65. Found: C, 83.65; H,6.47; N 4.49. v"" """'l725. 1580, 1475 cm". A 254 (34,400), 284(50.800), 341 (3,800),358 (3,800) m;:..

We claim:

1. A compound of the formula:

1. A COMPOUND OF THE FORMULA: